An autoimmune disease results from the failure of the immune system to maintain self-tolerance to antigen(s) in the affected organ. Over forty systemic and organ-specific autoimmune diseases have been observed, among which some, like systemic lupus erythematosus and myasthenia gravis, are mediated by antibodies, while others, such as multiple sclerosis (MS), insulin-dependent diabetes mellitus, rheumatoid arthritis and thyroiditis, are mediated by T-cells reactive against specific antigens in the relevant target organ. In the target organ, these abnormally activated T-cells initiate an inflammatory reaction whereby other T-cells, B-cells and macrophages as well as other mononuclear cells are recruited, resulting in organ-specific tissue damage.
Human autoimmune diseases can be divided into two broad categories: organ-specific and systemic autoimmune diseases.
Organ-specific autoimmune diseases include MS, insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis, several forms of anemia (aplastic, hemolytic), autoimmune hepatitis, thyroiditis, iridocyclitis, scleritis, uveitis, orchitis, myasthenia gravis, idiopathic thrombocytopenia purpura, and inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.
Systemic autoimmune diseases include scleroderma and systemic sclerosis, Sjogren's syndrome, undifferentiated connective tissue syndrome, antiphospholipid syndrome, different forms of vasculitis (polyarteritis nodosa, allergic granulomatosis and angiitis, Wegner's granulomatosis, Kawasaki disease, hypersensitivity vasculitis, Henoch-Schoenlein purpura, Behcet's Syndrome, Takayasu arteritis, giant cell arteritis, thromboangitis obliterans), systemic lupus erythematosus, polymyalgia rheumatica, psoriasis vulgaris and psoriatic arthritis, polymyositis and other idiopathic inflammatory myopathies, relapsing panniculitis, relapsing polychondritis, lymphomatoid granulomatosis, erythema nodosum, ankylosing spondylitis, Reiter's syndrome, and different forms of inflammatory dermatitis.
Several animal models have been developed to study autoimmunity. Among the autoimmune diseases, multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), have been thoroughly investigated as a prototypic organ-specific T-cell mediated autoimmune disease. MS is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by primary demyelination, which manifests itself clinically by varying degrees of neurological impairment in different patients. The disease is believed to result from an abnormal T-cell response to myelin antigens in the CNS.
Several myelin proteins have been identified as potential primary target antigens against which the deleterious autoimmune cells are directed, on the basis of their ability to cause EAE in laboratory animals (Kerlero de Rosbo and Ben-Nun, 1998). EAE, the purported experimental model for MS, presents many similarities in neuropathological and clinical manifestations with its human counterpart. EAE can be actively induced in genetically susceptible strains of laboratory animals by immunization with spinal cord homogenate, purified myelin proteins such as myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), or peptides thereof, emulsified in an adjuvant or passively induced by injection of activated CD4+ T-cell lines or clones specific for those myelin antigens (Kerlero de Rosbo and Ben-Nun, 1999). EAE induced in SJL/J mice with PLP 139-151 or in C3H.SW mice with MOG 35-55,is a severe chronic disease suitable for immunomodulatory studies (Kerlero de Rosbo and Ben-Nun, 1999).
Numerous immune-specific and non immune-specific approaches to therapy of autoimmune diseases have been investigated in experimental animal models. In the context of MS, some of these approaches have resulted in the development of drugs such as Copaxone and Interferon-β, the effectiveness of which in treatment of MS is limited.
Immune-specific approaches to therapy of autoimmune diseases have been thoroughly investigated. Among these, the administration of autoantigens has yielded promising results in rodents. Thus, injection and/or oral administration of MBP, MBP peptides, PLP peptides or whole myelin, could suppress the development of EAE in rodents, and oral administration of glutamic acid decarboxylase (GAD), S-antigen or collagen type II was effective in suppressing the development of diabetes, uveitis or rheumatoid arthritis, respectively, in laboratory animals. However, the results of a phase II clinical trial by oral feeding of MS patients with myelin were not encouraging.
One of the major difficulties in devising effective immune-specific therapy to autoimmune diseases is the complexity of the potentially deleterious autoimmune T-cell response whereby a multiplicity of autoantigens can be targeted. Accordingly, non immune-specific treatments via immunosuppressive agents such as corticosteroids, cyclosporin A, azathioprine, methotrexate etc, are often applied in MS, as well as in other autoimmune diseases. However, these treatments are often associated with “generalized immunosuppression” and side effects of varying severity in treated patients.
It would be very desirable to discover new agents that could be used for the therapy of autoimmune diseases and other immune-associated inflammatory disorders.